Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population.
Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population.
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DOI：
10.1371/journal.pone.0009287
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发表时间：
2010-02-18
期刊：
影响因子：
3.7
通讯作者：
Franceschi C
中科院分区：
文献类型：
--
作者：
Mishto M;Bellavista E;Ligorio C;Textoris-Taube K;Santoro A;Giordano M;D'Alfonso S;Listì F;Nacmias B;Cellini E;Leone M;Grimaldi LM;Fenoglio C;Esposito F;Martinelli-Boneschi F;Galimberti D;Scarpini E;Seifert U;Amato MP;Caruso C;Foschini MP;Kloetzel PM;Franceschi C
尽管多项研究指出 CD4+T 细胞在多发性硬化症中发挥关键作用，但 CD8+T 细胞参与病理学的研究仍处于早期阶段。蛋白酶体降解是产生 MHC I 类限制性表位的关键步骤，因此其活性可能是多发性硬化症中自身反应性 CD8+ T 细胞激活和调节的重要因素。免疫蛋白酶体和 PA28-αβ 调节剂存在于 MS 受影响的大脑区域并积聚在斑块中。它们在被认为参与多发性硬化症发展的细胞类型中表达，例如神经元、内皮细胞、少突胶质细胞、巨噬细胞/巨细胞和淋巴细胞。此外，在对 1262 例意大利 MS 病例和 845 例对照进行的基因研究中，我们观察到携带免疫蛋白酶体 LMP2 密码子 60HH 变体的 HLA-A*02+ 女性受试者患 MS 的风险降低。因此，携带 LMP2 60H 等位基因的免疫蛋白酶体在体外产生较低量的 HLA-A*0201 限制性免疫显性表位 MBP111-119。免疫蛋白酶体 LMP2 60HH 变体可降低意大利 HLA-A*02+ 女性患 MS 的风险。我们认为这种效应是由 MHC I 类上呈现的特定 MBP 表位的蛋白酶体依赖性产生改变介导的。因此，我们的观察结果支持免疫蛋白酶体参与 MS 发病机制的假设。
Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis. Immunoproteasomes and PA28-αβ regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP111–119. The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.
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影响因子：
5.6
作者：
Klare, Nicola;Seeger, Michael;Dahlmann, Burkhardt
通讯作者：
Dahlmann, Burkhardt
影响因子：
4.4
作者：
DEVLIN, B;RISCH, N
通讯作者：
RISCH, N
影响因子：
11.2
作者：
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通讯作者：
Wolinsky, JS
DOI：
10.1084/jem.20070064
发表时间：
2007-09-03
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Perry VH
影响因子：
82.9
作者：
Friese, Manuel A.;Jakobsen, Karen B.;Fugger, Lars
通讯作者：
Fugger, Lars